Immune mechanisms are responsible for a variety of maladies associated with a failure to mediate an effective immune response. Clinical circumstances that involve ineffective immune responsiveness include vaccination, vaccine failure, immunosuppression, immunodeficiency syndromes, viral infection, bacterial infection, fungal infection, parasitic infection, cancer initiation and progression, and Alzheimer's disease.
Immune checkpoint inhibition (ICI) is a mechanism involved in regulating immune responsiveness. Pardoll D., Nat Rev Cancer, 12, 252-264 (2012); Sharma P, Allison J P, Science 348, 56-61 (2015). This mechanism involves the surface membrane expression of molecules on immune cells, especially T lymphocytes, and their ligands on the surface membrane of other cells. The binding of ICI molecules transmits a negative immunoregulatory signal to T cells. In that way, immunity is down-regulated. ICI suppresses pathologic and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis.
It is well known that some compounds enhance autoimmune phenomena as an unwanted side effect of treatments for conditions not related to immunity. However, no one has proposed the possibility of using compounds that induce autoimmune phenomenon as a side effect for treatment of conditions that would benefit from enhanced immunity, even though many of the compounds have been known to induce autoimmune phenomena for more than 40 years.
Autoimmune phenomena as a side effect of therapy have never before been associated with immune potentiation. Autoimmunity has been considered an undesirable and pathological consequence of some therapies, and adverse events such as the induction of autoimmune phenomena have been shunned, not embraced. The possibility of developing a new therapy with a drug for another indication that causes an undesirable side effect has never before been achieved.
The autoimmune phenomena associated with immune checkpoint blockade have been characterized as “immune-related adverse events” and not seen as integral to treatment, even in the case of anticancer drugs. Autoimmune responses and physiological immune responses to infection and cancer and foreign substance have been taught as distinct which explains in part the novelty in proposing using compounds that induce autoimmune phenomena to enhance physiological immune responses.
In conditions such as chronic infection and neoplasia, ICI undesirably reduces the efficacy of an immune response capable of fighting the infection or eliminating the neoplasia. Immunotherapy for malignancies has involved the interruption of ICI. Thus, blocking antibodies that bind to cell surface components of ICI effectively turn off the inhibition of the immune response. Consequently, immunity is enhanced. Both the T cell surface receptors of ICI and their ligands have been successfully targeted with this approach. Autoimmune phenomena are a consequence of PD-1 blockade for patients with cancer. Michot et al., European J Cancer, 54:139-148 (2016). Most saliently, blocking antibodies to PD-1 or its ligand PD-L1 have enhanced anti-cancer immune responses in patients and resulted in significant remissions in the cancer. At present, the tumors that have shown responses to this therapy include melanoma, renal cell carcinoma, non-small cell lung cancer, small cell lung cancer, urothelial cancer, head and neck squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, esophageal cancer, colon cancer with high levels of microsatellite instability, all other tumors with high levels of microsatellite instability, Hodgkin lymphoma, non-Hodgkin lymphoma, ovarian cancer, mesothelioma, and triple negative breast cancer. Methods for modulating ICI suppressive activity are urgently required.